Inside FDA: When a drug is in short supply

Inside FDA: When a drug is in short supply
by Tamar Nordenberg

Infantile spasms, or West's syndrome, is a sometimes crippling
and even life-threatening seizure disorder that affects about 3,000
babies a year in the United States. The only drug that helps
prevent the spasms is Acthar gel (ACTH), and the drug's only
manufacturer is Rhone-Poulenc Rorer Pharmaceuticals Inc.

For several months in 1996, Rhone-Poulenc stopped making Acthar
because of manufacturing difficulties. A crisis resulted, with
insufficient supplies to treat patients with West's syndrome and
other diseases.

While the company worked with the Food and Drug Administration
to fix problems in its plant, the nonprofit National Organization
for Rare Disorders helped dole out the very limited supplies for
emergency cases of infantile spasms and other conditions. "During
the shortage, even some people with severe pain from rheumatoid
arthritis couldn't get the drug in favor of babies with
life-threatening West's syndrome," says NORD president Abbey
Meyers.

Severe drug shortages like this one are infrequent, but a minor
supply problem creating a potential shortage usually arises about
once or twice a month, says FDA's drug shortage coordinator, Mark
Goldberger.

Medical necessity

Potential drug shortages are a top agency priority, according to
Mark Lynch, a branch chief in FDA's division of drug manufacturing
and product quality. "Shortages call for rapid communication among
the key people within FDA," he says. "Those involved have to drop
what they're doing and react rapidly to the crisis."

But a reduction in the drug supply doesn't always warrant this
emergency status. To be defined as a high-priority drug shortage,
the drug must be found to be "medically necessary." The FDA
division responsible for the drug leads the determination of
medical necessity. The division considers several factors,
including:

the opinion of health professionals about the drug's
usefulness

the seriousness of the medical condition

the availability of acceptable brand-name or generic
alternatives.

For example, a dangerous drug shortage occurred a few years ago
when the supply of the anemia drug Desferal (deferoxamine mesylate)
suddenly dropped. Desferal is the standard treatment for a fatal
blood disease called Cooley's anemia. In 1995, an FDA inspection
uncovered some manufacturing problems at the Swiss facility of the
former Ciba-Geigy Corp., the only plant where Desferal was made,
leading to a plant shutdown.

"We were fearful about the potential danger to patients based on
the fact that there was no alternative source for Desferal," says
Gina Cioffi, national executive director of the Cooley's Anemia
Foundation. "Our patients must use this drug every day or they're
taking time off their life as iron builds up in their blood."

In a drug shortage situation like the one involving Desferal,
FDA takes steps to find alternative sources of the drug or control
the distribution to make sure the most needy patients have access
to it.

"These are acute problems that need to be addressed swiftly,
with either a resolution or a short-term fix," Goldberger says. "If
you've got a drug like Acthar that you need to prevent mental
retardation or a drug like Desferal that you need to prevent iron
overload, you can't take years. You either have to make it
available quickly or figure out a substitute drug."

Increasing the supply

The review division and office of compliance in FDA's Center for
Drug Evaluation and Research work with manufacturers and third
parties to find ways to keep a drug available despite various
obstacles. "It's a problem-solving exercise," Lynch says. "Each
situation is different, each drug is different, and the people are
different each time."

The Acthar gel shortage was "different" because the drug is made
from animal pituitary glands. "Because it is not synthetic, it is a
difficult drug to manufacture," Goldberger says. "We worked with
Rhone-Poulenc to bring the product to market while not placing an
unrealistic burden on the company."

Sometimes FDA must take steps to avoid a drug shortage when the
agency takes regulatory action, such as seizure or injunction,
against a company. If shutting down a plant while the manufacturer
corrects problems could lead to a shortage of a medically necessary
drug, the agency may exempt that drug from the ban to keep it
available.

To decide whether to make an exception for a certain drug, FDA
must balance two risks: the risk from the noncompliance--for
example, a manufacturing violation could result in a slightly less
potent medication--and the risk of not having the product available
at all.

For example, in spite of manufacturing problems, FDA allowed
Ciba-Geigy's Desferal (as well as two other medically necessary
drugs) into the United States from the firm's Swiss facility. FDA
compliance officer Richard Friedman checked the quality of each lot
of Desferal entering the country by analyzing extra data submitted
by the company. "We worked closely with the firm to assure that
products made it to pharmacies without delay and with no sacrifice
in quality," Friedman says.

In other cases, a manufacturer may decide to stop making a drug
simply because it is not a money-maker. In these cases, FDA or the
National Organization for Rare Disorders may speak with other
companies about making up the void. "To a big company, a market of
$10 million or $20 million usually isn't enough," says NORD
president Meyers, "but to a small company, that market might be
attractive." (See accompanying article.)

Other times, because of poor planning or an unforeseeable event
such as a plant explosion or fire, a company may not have the usual
amount of time required to get agency approval of a manufacturing
change, such as a move to a new plant. If an interruption in
manufacturing may lead to a dangerous drug shortage, FDA can
expedite its inspection of the new plant or its review of required
applications.

In cases where a company is experiencing a temporary delay in
production, FDA may talk to other companies who have the facilities
to make the product short-term, or the agency may see if the
manufacturer has some extra stock in its plant or warehouse that
can help bridge the gap.

Managing the demand

When a product is in dangerously short supply, the manufacturer
or another party may set up an allocation program. That way, the
drug is shipped directly to those who need it, rather than being
shipped in large quantities to sit in a warehouse.

"Without a controlled allocation program," Goldberger says,
"it's kind of like a gasoline shortage. Everyone rushes out and
keeps their tanks full, and by keeping their tanks full, there's
less gasoline to go around for those who really need it. If people
just filled up when they needed to, you might not have a
shortage."

To make sure anemic patients possessed only the amount of
Desferal they really needed, Ciba-Geigy set up a distribution
schedule to ensure that pharmacies only gave out a two-week supply
at a time. "The company responded quickly by coming up with a
distribution plan to make sure there was no gap in getting patients
their drug," says Cioffi.

Shared responsibility

Usually, dire shortages that require rationing can be avoided.
Communication with the company and with specialized organizations
such as NORD is the key, according to Goldberger.

The earlier FDA becomes aware of a possible shortage of a
critical drug, the more effectively the agency can deal with it.
"Part of the responsibility lies with the companies," Friedman
says. "They should inform us as soon as possible if they anticipate
a shortage of a medically necessary product."

FDA can sometimes help to avert a crisis or minimize the harm to
patients if a shortage does occur. But, Goldberger says, "There are
certain steps you have to go through to manufacture a product and
get a product out on the market. FDA can speed up the process--find
bridges--but we can't abolish it altogether or we couldn't be sure
of the drug's quality."

No shortage of incentives

The Orphan Drug Act, a 1983 addition to the Federal Food, Drug,
and Cosmetic Act, offers financial incentives to the developer of a
drug for a rare disease, including tax credits for clinical
research and a seven-year period of exclusive marketing. FDA's
Office of Orphan Products Development identifies orphan products
and aids their development with guidance and grants. A rare disease
is one that affects fewer than 200,000 Americans or a population so
small that U.S. sales would not cover the cost of developing the
drug. There are 5,000 such diseases, which affect a total of 20
million Americans, according to Abbey Meyers, president of the
National Organization for Rare Disorders.

"The act has been very successful in attracting companies,"
Meyers says. Since its passage in 1983, FDA has approved more than
140 drugs for rare conditions, compared to only 10 such approvals
in the decade before 1983.

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